1. Field of the Invention
This invention relates to use of coatings on medical devices for the purpose of down-regulating complement activation. The present invention relates to methods for modifying medical devices, including those having inorganic or metal surfaces, for the purpose of improving biocompatibility. The invention also relates to methods for attaching bioactive compounds to the surface of a medical device that may have a therapeutic effect and or improve the function of the device.
2. Description of the Related Art
The implantation of medical devices and/or other biomaterials in a body can result in injury and initiation of the inflammatory response. The complement and coagulation systems can play a role in a body's acceptance or rejection of a medical device.
Both the complement and coagulation systems comprise a complex set of proteins that when activated, exert their effects through a cascade of protein-protein and protein-cell interactions. The complement system is a certain part of the immune system and helps to protect the body from invading pathogens. The complement system comprises three pathways: the classical pathway, the alternative pathway, and the lectin pathway [1]. These pathways proceed differently in their initial steps but they converge at the level of C3 to share the same terminal components that result in the attack of target cells. In addition to producting terminal complexes that are capable of lysing target cells, activation of the complement cascades results in production of inflammatory mediators and stimulation of inflammitory cells. The classical pathway is triggered by antibody recognition, whereas, the alternate pathway is antibody independent and can be initiated by certain surface markers on pathogen cells. The alternate pathway is thought to be the major contributor to inflammation associated with blood material interactions. However, evidence exists that the classical pathway can also contribute [2-4]. For this reason, an ideal modulator of material induced inflammation would provide for down-regulation of both pathways.
Increasing knowledge about the underlying factors that contribute to many types of inflammatory diseases, transplantation rejection, sepsis and systemic inflammatory response syndrome (SIRS) has triggered a wide spread effort to identify therapeutic targets for both the complement and coagulation systems. Both natural and synthetic regulators of these systems have been identified in a variety of forms including proteins, peptides, antibodies, oligonucleotides, and synthetic molecules [5-19]. A peptide of particular interest is compstatin [4]. Natural regulators of complement activation (RCA) include factor H, factor H like protein 1 (FHL-1), factor H related proteins (FHR-3, FHR-4), C4 binding protein (C4bp), complement receptor 1 (CR1), decay-accelerating factor (DAF), and membrane cofactor protein (MCP). Under normal conditions, these proteins keep the activation processes of complement in check and all have been considered in one form or another as potential treatments for immune system dysfunctions. Certain types of viruses produce complement regulatory proteins as a means of evading the human immune system. Two regulators of interest due to their high potency are vaccinia virus complement control protein (VCP) and small pox inhibitor of complement enzymes (SPICE) [20].
Biomaterials used for medical devices act as substitutes for natural tissue. Compatibility characterizes a set of material specifications which address the various aspects of material-tissue interactions. More specifically, hemocompatibility defines the ability of a biomaterial to stay in contact with blood for a clinically relevant period of time without causing alterations of the formed elements and plasma constituents of the blood or substantially altering the composition of the material itself.
Cardiovascular devices and extracorporeal circulation (ECC) devices come into contact with large volumes of blood. This contact initiates an inflammatory reaction that is responsible for many adverse side effects [21, 22]. The type and severity of side effects depends on a number of factors including the type of device and procedure, the patient's susceptibility to inflammation, and the biocompatibility of the materials from which the devices are constructed [23]. Many of these factors can not be controlled. However, by improving the hemocompatibility of materials used to construct the blood contacting surfaces of these devices, it is possible substantially decrease side effects and improve patency.
In the case of cardiovascular devices, the most serious side effect of blood-material contact is activation of the coagulation cascade and thrombus formation. However, it is now clear that side effects associated with complement activation and inflammation also play a major role in determining the long term success of these devices. For example, restenosis after stent placement occurs in 8% to 80% of patients within 6 months depending on both anatomic and clinical risk factors [24]. Stent implantation results in early deendothelialization, injury to smooth muscle cells and thrombus deposition. With time, this leads to smooth muscle cell proliferation, migration and deposition of extracellular matrix. In some patients this process occur in excess and leads to neointimal growth and narrowing of the artery lumen. Inflammation plays a pivotal role in this process, where activated inflammatory cells secrete factors that stimulate smooth muscle cell growth and matrix deposition. Methods that can reduce inflammation associated with stent implantation may reduce the incidence of restenosis.
Side effects associated with ECC procedures including cardiopulmonary bypass, plasmapheresis, plateletpheresis, leukopheresis, LDL removal, hemodialysis, ultrafiltration, and hemoperfusion, stem from a series of events that occur when blood contacts artificial materials including, but not limited to, adsorption of plasma proteins, platelet adhesion and activation, activation of the complement and coagulation cascades, and activation of leukocytes. These events can lead to a systemic inflammatory response and can cause serious complications. Examples of complications include, but are not limited to, myocardial dysfunction, respiratory failure, renal and neurological dysfunction, bleeding disorders, altered liver function, and multiple organ failure. Systemic inflammation is also thought to play role in the accelerated arteriosclerosis that is commonly observed in hemodialysis patients [25-28]. Furthermore, many patients who are in need of hemodialysis or hemofiltration already have compromised immune systems. For example, approximately 20% of sepsis patients require hemodialysis. Unfortunately, although the dialysis can be successful in removing toxins from the patient's blood, it can simultaneously, further exacerbate the patient's inflammatory condition.
The majority of therapeutics for immune disorders are developed for systemic administration. Because ECC causes dysfunctions of the same systems, many of these therapeutics have also been considered as treatments for patients undergoing ECC, most notably, cardiopulmonary bypass [18, 23, 29]. However, there are limitations and side effects associated with systemic delivery of these therapeutics; the patient's immune system can be compromised, leaving them at greater risk for infection, or they can be put at risk for serious bleeding.
To this end, much work has been done to improve a material's hemocompatability for medical devices and these approaches more or less fall into two main categories. In the first category, materials have been modified to make them inert. This has largely been accomplished by modifying the materials with hydrophilic polymers such as PEO [18, 23, 29-38]. The intent here has been to inhibit protein adsorption and platelet adhesion to the device and thereby minimize activation of the complement and coagulation cascades. A limitation of this type of approach is the inability to attach a sufficient amount of hydrophilic polymer to the device surface without altering the material's bulk properties, or in the case of dialysis, without altering the device's ability to remove toxic components from the blood. It has also proven difficult to modify the surfaces of some types of materials due to an inability to impart needed functional groups. In the second category, proteins, peptides or carbohydrates have been applied to the device surface that have the capacity to down regulate the complement or coagulation cascade [39, 40]. Within this category, the most widely used approach has been to modify materials with heparin. Here, the device displays a therapeutic component, however, depending on the protein or peptide used for coating, the primary source of the problem, namely nonspecific blood-material interactions, can still persist and the side effects that result from those interactions may not be completely offset by the therapeutic factor. Furthermore, some methods that can be used to activate materials to allow for coupling to therapeutic proteins or peptides can, in of themselves, promote complement activation [39]. Both types of approaches have shown some improvement over their unmodified counterparts in experimental systems; however, solid improvements in clinical outcomes remain questionable and further improvements to materials for medical devices are very much needed.
Methods for modifying the surfaces of medical devices with passivating molecules such as polyethylene oxide (PEO) have been described. These methods have been shown to reduce protein adsorption and platelet adhesion. One prior art method involves modifying inorganic and metal substrates to incorporate PEO chains by first silanizing the metal, second exposing the metal to a hydrophilic polymer or block copolymer containing one or more hydrophilic blocks or other passivating molecule, and third causing the formation of a covalent bond between the silane layer and the passivating molecule by for example, applying UV or gamma irradiation. A similar approach involving the application of UV activatable silane reagents has been used to covalently bond polymeric films to silicone wafers (Prucker et al., 1999).
A major limitation of prior art methods is the inability to attach additional molecules to the substrate after it has been modified with a passivating molecule. Caldwell et al have described a method for applying a passivating coating to surfaces, while simultaneously, incorporating functional groups that could be used to specifically immobilize proteins or other biomolecules (U.S. Pat. No. 5,516,703). However, the method of Caldwell et al. utilizes its application to hydrophobic surfaces, primarily those that are polymeric.